1. Field of the Invention
The present invention relates generally to the field of therapeutics and in particular, chemotherapeutics and formulations useful for same. Even more particularly, the present invention provides therapeutic strategies which reduce the toxicity or enhance the efficacy of therapeutic agents. Compositions, methods of treatment and prophylaxis and therapeutic protocols are also contemplated by the present invention.
2. Description of the Prior Art
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in any country.
Drug toxicity is a major limitation in the administration of therapeutic compounds. In order to achieve and maintain a therapeutic concentration of the active drug substance at and within the pathological site it is necessary to administer high doses of the chemotherapeutic agent. Systemic toxicity is frequently the end result, therefore in an attempt to alleviate systemic toxicity the clinician will administer sub-optimal doses of the therapeutic agent where there is an intricate balance between therapeutically active and non-toxic drug dosage. As a consequence of this compromised but balanced drug regimen, there is often sub-optimal therapeutic serum levels of a given therapeutic compound being available to a patient. Observed toxicity may result in limiting the frequency of dosing, the quantum of dosing or the number of cycles of dosing.
An example of one such therapeutic substance which is associated with significant toxicity is Irinotecan hydrochloride (CPT-11; Camptosar®. CPT-11) which is a water soluble derivative of camptothecin, a plant alkaloid with anti-tumor activity, originally isolated from Camptotheca acuminata. CPT-11 has a wide spectrum of anti-tumor activity and has been shown to be effective for the treatment of refractory colorectal cancer, for which CPT-11 chemotherapy has been approved worldwide.
During CPT-11 chemotherapy, the main dose limiting toxicities are delayed diarrhea and myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased. This condition leads to fewer red blood cells, white blood cells, and platelets which generally manifests as a lowered immune system and a greater prevalence to primary and secondary bacterial and/or fungal infections. The duration of myelosuppression can be partially controlled by the administration of granulocyte colony stimulating factor but this therapeutic approach is represents a high cost of treatment as well as an invasive and extended hospitalization period for the patient. Diarrhea affects the quality of life and when combined with myelosuppression can be life threatening.
CPT-11 is converted in vivo by hepatic carboxylesterase to form the active metabolite SN-38, a potent inhibitor of topoisomerase I, a nuclear enzyme critical in the process of DNA replication and transcription. In the liver, a portion of the SN-38 undergoes subsequent detoxification by glucuronidation by the UDP-glucuronysyltransferase system with the formation of inactive SN-38G. Biliary excretion represents the major elimination pathway for CPT-11 and its metabolites. Once in the intestine SN-38G can be deconjugated via bacterial or tissue beta-glucuronidase mediated cleavage to SN-38, resulting in local irritation and toxicity to the gut (Takasuna et al. Cancer Res 56:3752-3757, 1996). From the bowel CPT-11 and its metabolites may also be reabsorbed via intestinal cells and form an enterohepatic recirculation loop (Takasuna et al. 1996 supra).
Accordingly, although therapeutic agents are currently available which, if administered at optimal doses would be capable of treating diseases, such as cancer, infection by pathogens, the treatment of pain, gastrointestinal disorders and neurological conditions amongst many other conditions, there exists a need for compositions and therapeutic strategies which reduce debilitating side effects and/or which promote the generation of particularly efficacious forms of the therapeutic agents.